Focal adhesion kinase regulates smooth muscle cell recruitment to the developing vasculature.
Focal adhesion kinase regulates smooth muscle cell recruitment to the developing vasculature.
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DOI：
10.1161/atvbaha.111.232231
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发表时间：
2011-10
期刊：
影响因子：
--
通讯作者：
Taylor JM
中科院分区：
文献类型：
--
作者：
Cheng Z;Sundberg-Smith LJ;Mangiante LE;Sayers RL;Hakim ZS;Musunuri S;Maguire CT;Majesky MW;Zhou Z;Mack CP;Taylor JM
新形成的内皮管与分化的平滑肌细胞（SMC）的投资对于适当的血管形成至关重要，但潜在的机制尚不清楚。我们之前的研究表明，nkx2.5表达域的局灶黏附激酶（FAK）的缺失会导致流出道（OFT）形态发生异常，并在此努力确定所涉及的细胞类型和机制。我们将fakloxp靶向小鼠与可用的Cre驱动程序杂交，以消耗OFT SMC （FAKwnt和FAKnk）或冠状动脉SMC （FAKcSMC）中的FAK。在每种情况下，FAK的消耗都会导致与产后生活不相容的血管生成缺陷。突变血管结构的免疫组织化学分析显示，FAK不是祖细胞增殖、存活或向SMC分化所必需的，但对于随后的SMC募集形成脉管系统是必要的。利用一种新的无FAK的SMC培养模型，我们发现FAK的消耗不会影响SMC的生长或存活，但会阻止SMC向内皮来源的趋化因子PDGFBB的定向运动和侵袭。由于小GTPase， Rac-1的时空激活缺陷以及缺乏依赖于rac1的皮质蛋白（一种肌动蛋白稳定蛋白）向边缘的募集，FAK缺失导致不稳定的板足突。此外，FAK无效SMC显示pdgf刺激的细胞外基质降解显著减少。FAK驱动pdgfbb刺激的SMC趋化/侵袭，是SMC适当填充主动脉肺间隔和冠状动脉血管丛的必要条件。
The investment of newly formed endothelial cell tubes with differentiated smooth muscle cells (SMC) is critical for appropriate vessel formation, but the underlying mechanisms remain unknown. We previously showed that depletion of focal adhesion kinase (FAK) in the nkx2.5 expression domain led to aberrant outflow tract (OFT) morphogenesis and strove herein to determine the cell types and mechanisms involved. We crossed fakloxp targeted mice with available Cre drivers to deplete FAK in OFT SMC (FAKwnt and FAKnk) or coronary SMC (FAKcSMC). In each case, depletion of FAK led to defective vasculogenesis that was incompatible with post-natal life. Immunohistochemical analysis of the mutant vascular structures revealed that FAK was not required for progenitor cell proliferation, survival, or differentiation into SMC, but was necessary for subsequent SMC recruitment to developing vasculature. Using a novel FAK-null SMC culture model, we found that depletion of FAK did not influence SMC growth or survival, but blocked directional SMC motility and invasion toward the potent endothelial-derived chemokine, PDGFBB. FAK depletion resulted in un-stable lamellipodial protrusions due to defective spatial-temporal activation of the small GTPase, Rac-1 and lack of Rac1-dependent recruitment of cortactin (an actin stabilizing protein) to the leading edge. Moreover, FAK null SMC exhibited a significant reduction in PDGF-stimulated extracellular matrix degradation. FAK drives PDGFBB-stimulated SMC chemotaxis/invasion and is essential for SMC to appropriately populate the aorticopulmonary septum and the coronary vascular plexus.